title: Aryl hydrocarbon receptor-dependent retention of nuclear HuR suppresses cigarette smoke-induced cyclooxygenase-2 expression independent of DNA-binding.
abstract: The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to man-made environmental toxicants, has emerged as an endogenous regulator of cyclooxygenase-2 (Cox-2) by a mechanism that is poorly understood. In this study, we first used AhR-deficient (AhR(-/-) ) primary pulmonary cells, together with pharmacological tools to inhibit new RNA synthesis, to show that the AhR is a prominent factor in the destabilization of Cox-2 mRNA. The destabilization of Cox-2 mRNA and subsequent suppression of cigarette smoke-induced COX-2 protein expression by the AhR was independent of its ability to bind the dioxin response element (DRE), thereby differentiating the DRE-driven toxicological AhR pathway from its anti-inflammatory abilities. We further describe that the AhR destabilizes Cox-2 mRNA by sequestering HuR within the nucleus. The role of HuR in AhR stabilization of Cox-2 mRNA was confirmed by knockdown of HuR, which resulted in rapid Cox-2 mRNA degradation. Finally, in the lungs of AhR(-/-) mice exposed to cigarette smoke, there was little Cox-2 mRNA despite robust COX-2 protein expression, a finding that correlates with almost exclusive cytoplasmic HuR within the lungs of AhR(-/-) mice. Therefore, we propose that the AhR plays an important role in suppressing the expression of inflammatory proteins, a function that extends beyond the ability of the AhR to respond to man-made toxicants. These findings open the possibility that a DRE-independent AhR pathway may be exploited therapeutically as an anti-inflammatory target.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Michela
authors.initials: M
authors.lastname: Zago
authors.forename: Jared A
authors.initials: JA
authors.lastname: Sheridan
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Nair
authors.forename: Angela
authors.initials: A
authors.lastname: Rico de Souza
authors.forename: Imed-Eddine
authors.initials: IE
authors.lastname: Gallouzi
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.forename: Sergio
authors.initials: S
authors.lastname: Di Marco
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: David H
authors.initials: DH
authors.lastname: Eidelman
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D051959:ELAV Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D011453:Prostaglandins / Q000096:biosynthesis; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D051959:ELAV Proteins; D011453:Prostaglandins; D011720:Pyrazoles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D004247:DNA; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2